Immunoregulatory treatment for minimal change nephrotic syndrome.

Immunological studies were performed in 18 children with minimal change nephrotic syndrome proved by biopsy examination during relapse and in 15 age matched controls. All 18 children showed dysfunction of cell mediated immunity as evidenced by low absolute lymphocyte count, low blastogenesis index in response to phytohaemagglutinin stimulation, and reduced skin sensitivity to dinitrochlorobenzene when compared with controls. All 18 patients had low serum IgG concentrations, while the IgA, IgM, and C3 concentrations in the serum were within normal limits. Based on the evidence of depressed cell mediated immunity, 14 patients with nephrotic syndrome were treated with an immunoregulatory drug l-tetramisole (levamisole) for a period of 20-24 weeks. Six patients went into complete remission within 4-20 weeks of treatment, a further six patients went into partial remission, while two did not respond. On follow up (six to 24 months after stopping levamisole), of the six patients who achieved complete remission, four continued to maintain the state and two relapsed after roughly six months. Of the six patients who achieved partial remission, two went into complete remission, two continued to be in partial remission, and two relapsed.     

Obesity exacerbates sepsis-induced inflammation and microvascular dysfunction in mouse brain

OBJECTIVE: Obese patients with sepsis have higher morbidity and mortality than lean counterparts, but the mechanisms involved are unknown. The authors examined the inflammatory and thrombogenic responses of the cerebral microvasculature to sepsis induced by cecal ligation and perforation in obese and lean wild-type mice. METHODS: Leukocyte and platelet adhesion in cerebral microvasculature and behavioral responses were measured in wild-type and obese mice 4 h postperforation. P-selectin expression in different vascular beds was assessed 6 h postperforation. The effects of immunoblockade of P-selectin, ICAM-1, and CD18 on leukocyte and platelet recruitment were evaluated in obese septic animals. RESULTS: Cerebral venules of obese and wild-type mice assumed a proinflammatory and prothrombogenic phenotype 4 h post-perforation, with greatly exaggerated responses in obese mice compared to the lean counterparts. These enhanced responses were attenuated by blocking P-selectin, CD18, or ICAM-1. Obese mice also exhibited a more profound behavioral deficit after sepsis, which appears to be unrelated to the recruitment of leukocytes and platelets. Cecal ligation and perforation-induced P-selectin expression was greater in obese mice compared with lean counterparts. CONCLUSIONS: These findings suggest that the increased morbidity to sepsis in obesity may result from exaggerated microvascular inflammatory and thrombogenic responses that include the activation of endothelial cells with subsequent expression of adhesion molecules, such as P-selectin.     

Dopamine transporter as target for drug development of cocaine dependence medications

Because much evidence implicates the dopamine transporter in the reinforcing effects of cocaine, development of potential medications for cocaine dependence has included the dopamine transporter as a target. The present overview covers progress in the drug development area regarding several classes of dopamine uptake inhibitors, with an emphasis on structure-activity relationships that enhance potency and selectivity at transporters for dopamine compared with those for serotonin or norepinephrine. The following categories of compounds are covered: tropane, benztropine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR), methylphenidate, mazindol, and phencyclidine analogs. Activity at transporters as well as on behavior is highlighted.     

Modulation of circulating cell–endothelial cell interaction by erythropoietin in lean and obese mice with cecal ligation and puncture

Objective: Septic shock related morbidity is increased further in obese patients. Obese mice have exaggerated inflammatory response compared to lean mice when exposed to cecal ligation and puncture (CLP). The current study employs use of erythropoietin (EPO), an anti-inflammatory agent in obese and lean mice with CLP to study inflammation. Method: Intravital videomicroscopy was used to quantify CLP-induced platelet (PA) and leukocyte (LA) adhesion in cerebral microcirculation of WT (C57Bl/6) and ob/ob (B6.V-Lepob/J) mice with or without EPO (500 units/kg) treatment. P-selectin expression (P-sel) in various tissues, blood–brain barrier (BBB) and behavioral function and serum tumor necrosis factor (TNF) levels were quantified in these animals. LA, PA, BBB function and P-sel were measured in TNF monoclonal antibody (mAb) pre-treated ob/ob mice. Results: EPO attenuated the LA, PA, BBB and behavioral dysfunctions and serum TNF levels 4 h after CLP in both WT and ob/ob mice, and P-sel in ob/ob CLP mice. Furthermore, TNF mAb and EPO decreased the LA, PA, BBB dysfunction and P-sel in the ob/ob CLP animals to the same degree. Conclusion: EPO exerts significant anti-inflammatory actions in obese and lean septic mice. Modulation of P-selectin expression via attenuation of TNF production is a suggested underlying mechanism.     

Hypertonic saline and the cerebral microcirculation in obese septic mice

OBJECTIVES: Increased morbidity and mortality in critically ill obese patients may result from an exaggerated inflammatory response and/or a diminished effectiveness of routine therapeutic strategies used in the critical care setting. The objectives of this study were to compare the effectiveness of hypertonic saline (HTS) resuscitation in obese and lean mice with sepsis and to address potential mechanisms underlying HTS-mediated protection against the inflammatory and microvascular responses to sepsis. METHODS: Intravital videomicroscopy was used to monitor and quantify the adhesion of platelets and leukocytes in the brain microcirculation of WT (C57 Bl/6) and ob/ob (B6.V-Lepob/J) mice subjected to cecal ligation and puncture (CLP) and resuscitated with either normal saline or HTS. The dual radiolabeled monoclonal antibody method was used to measure P-selectin expression in the microcirculation, while the sepsis-induced behavioral deficit was quantified using a multicompartment chamber test. RESULTS: HTS attenuated the accumulation of adherent leukocytes and platelets and the behavioral deficit observed at 4 h after CLP in both WT and ob/ob mice. CLP-induced upregulation of P-selectin in the brain microcirculation was attenuated by HTS in ob/ob, but not in lean, mice. CONCLUSION: HTS exerts significant anti-inflammatory and anti-thrombogenic actions in obese septic mice. These responses may be related to the inhibitory effect of HTS on sepsis-induced P-selectin expression.     

Cystic Granular Cell Ameloblastoma

Ameloblastoma is a locally aggressive benign epithelial odontogenic tumor, while unicystic ameloblastoma is a relatively less aggressive variant. Although rare in unicystic or cystic ameloblastoma, granular cell change in ameloblastoma is a recognized phenomenon. The purpose of the present article is to report a case of cystic granular cell ameloblastoma in 34-year old female.     

Confirm Rx insertable cardiac monitor for primary atrial fibrillation detection in high-risk heart failure patients (Confirm-AF trial)

Background

Patients with heart failure (HF) represent a large population of patients who are at high risk for complications related to undiagnosed atrial fibrillation (AF). However, currently there are limited modalities available for early AF detection in this high-risk population. An implantable cardiac monitor (ICM) is inserted subcutaneously and can provide long-term arrhythmia information via remote monitoring.

Methods and Results

Confirm-AF is a prospective randomized, nonblinded, two arm, multicenter clinical trial to be performed in the United States, enrolling 477 patients with a history of HF hospitalization and left ventricular ejection fraction >35% from 30 medical sites. Patients will be randomized in a 2:1 fashion to undergo ICM implant with remote monitoring and symptom-triggered mobile app transmissions versus (vs.) Non-ICM management and follow-up. The primary objective of this trial is to compare the time to first detection of AF lasting > 5 min using an Abbott ICM compared to non-ICM monitoring in symptomatic HF patients. This article describes the design and analytic plan for the Confirm-AF trial.

Conclusions

The Confirm-AF trial seeks to accurately define the burden of AF in high-risk HF patients with LVEF > 35% using an Abbott ICM. A finding showing significantly higher incidence of AF along with improved clinical outcomes with ICM monitoring is expected to have substantial clinical implications and may change the method of monitoring high-risk HF patients.